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Hobson    apps in interventional cardiology Hobson apps in interventional cardiology Document Transcript

  • Platelets, December 2006; 17(8): 509–518REVIEWThrombelastography: Current clinical applications and its potential rolein interventional cardiologyA. R. HOBSON, R. A. AGARWALA, R. A. SWALLOW, K. D. DAWKINS, & N. P. CURZENSouthampton University Hospital, Wessex Cardiac Unit, Southampton, UK(Received 28 March 2006; accepted 25 July 2006)AbstractThrombelastography is a bedside blood test used to assess patients’ haemostatic status. It has a well-established role inhepatobiliary and cardiac surgery and is also used in obstetrics and trauma medicine to assess coagulation and identify thecauses of post-operative bleeding. It is not routinely used in the diagnosis or treatment of thrombosis although recently ithas been shown to predict thrombotic events post-operatively and after percutaneous intervention (PCI). In cardiovascularmedicine the importance of the platelet in the pathophysiology of vascular events is increasingly apparent. As a resultantiplatelet therapy is a cornerstone of the treatment for coronary disease, particularly in the setting of acute coronarysyndromes. The increasing utilization of stents, particularly drug-eluting devices, in PCI has also necessitated widespreaduse of antiplatelet agents to minimize the risk of stent thrombosis. A quick, accurate and reliable test to measure the effectof platelet inhibition by antiplatelet agents on clotting in an individual patient would be of profound clinical value. Theresults from such a test could provide prognostic information, allow treatment with antiplatelet agents to be tailored to theindividual and identify resistance to one or more of these agents. Optimization and tailoring of anti-platelet therapy inpatients with cardiovascular disease, particularly those undergoing PCI, using such a test may reduce morbidity andmortality from thrombotic and haemorrhagic complications. Current methods of assessing platelet activity measure plateletcount and function in isolation. Optical aggregation is the most widely used method for assessing platelet function but it isrelatively time consuming, measures platelet function in isolation rather than in the context of clot formation and is not abedside test. By contrast the modified thrombelastograph platelet mapping kit marketed by Haemoscope can be used toassess the effects of antiplatelet agents on ex vivo blood clotting, thus giving a measurement more relevant to in vivoresponses. This represents a potentially powerful tool to assess response of individual patients to antiplatelet therapy,particularly in the context of PCI.Keywords: Platelets, clotting, vascular, aspirin, clopidogrelIntroduction Principles of TEGÕ : The test and how it works Kaolin activated blood at 37 C is placed in aThe ThrombelastographÕ (TEGÕ ) Haemostasis cylindrical cuvette (cup) that oscillates by 4 degreesSystem (Haemoscope Corp, IL, USA) provides an 450 at a frequency of 0.1 Hertz. Suspended within theoverall assessment of haemostatic function [1, 2]. It cup by a torsion wire is a stationary pin. As the cupprovides a graphic representation of clot formation oscillates there is a 1 mm gap between it and the pin.and lysis. First developed in 1948, it was used The wire acts as a torque transducer [5, 6]initially as a research tool [3]. In the last 20 years (Figure 1).development and automation of TEGÕ has facili- When whole blood is in its liquid form cuptated its utility in the clinical management of oscillation has no impact on the pin. As blood clots,bleeding and haemostasis where it is used to guide fibrin strands link the pin and the cup and changes inclotting factor replacement, platelet transfusion and the viscoelasticity of the blood are therefore trans-in fibrinolysis treatment [4]. Recent modifications mitted to the pin. The resulting torque generates anhave further added to its potential applications. electrical signal whose magnitude can be plotted as aCorrespondence: N. P. Curzen, PhD FRCP FESC, Consultant Cardiologist and Hon. Senior Lecturer, Wessex Cardiac Unit, Southampton UniversityHospital, Southampton SO16 6YD, UK. Tel: þ44 (0)2380 794972. Fax: þ44 (0)2380 794772. E-mail: nick.curzen@suht.swest.nhs.ukISSN 0953–7104 print/ISSN 1369–1635 online ß 2006 Informa UK Ltd.DOI: 10.1080/09537100600935259
  • 510 A. R. Hobson et al.function of time to produce a TEGÕ trace [5, 7] provide continuous real time information on the(Figure 2). Thus, as blood clots there is a progressive viscoelastic properties of the evolving clot from theincrease in the signal amplitude to a maximum. The time of initial fibrin formation, through plateletstandard TEGÕ trace can be analysed to provide aggregation, fibrin cross linkage and clot strengthen-several parameters defining the speed and strength of ing to clot lysis [8]. Analysis can determine a) theclot formation (Table I). Normal haemostasis speed of clot generation, b) its strength and c) itsinvolves the controlled activation of clot formation, stability [9].spontaneously balanced by mechanisms of clot lysis; Clotting is a dynamic process. Conventional teststherefore a truly global analysis of haemostatic such as activated partial thromboplastin timefunction requires assessment of both the fibrinolytic and platelet count and function assess isolatedand coagulation systems. TEGÕ measurements components of the haemostatic system and areincorporate both of these components by using the unable to predict the role of these components inparameter of viscoelasticity of clotting blood. This the context of haemostasis as a whole. The advantageassessment is dependent on a) cellular and plasma of TEGÕ is that it incorporates the interaction of allcomponents b) the activity and concentration ofcoagulation elements as well as c) procoagulant andd) fibrinolytic activity. The TEGÕ trace can therefore Table I. Commonly assessed TEGÕ Parameters. Description and rationale Parameter for assessment R time Reflects the time to initial fibrin formation. Relates to plasma clotting factor and inhibitor activity. K time The time taken for the blood to achieve a fixed level of viscoelasticity. Assesses the rapidity of fibrin cross linking. angle The angle formed by the gradient of the initial trace. Represents the speed of clot formation. MA (maximum This indicates the strength amplitude) of the clot and reflects the activity of fibrin and platelets. Area under Is dependent on both the MA andFigure 1. How TEG works: blood is added to a cup into which a TEGÕ curve angle and therefore incorporates bothpin is placed. The cup oscillates. Forming clot transmits the the strength and speed of clot formation.Figure 2. A TEG trace. The time to initial clot formation, rate of clot formation (initial angle of trace) and the strength of the clot(maximum amplitude of the trace) can all be established.
  • Thrombelastography 511of the components of coagulation including platelets, activators and activators of fibrin formation) allowfibrin, clotting factors, and thrombin as well as the effects of antiplatelet therapies to be detected andproviding information about the quality of the clot whilst summarized in Table II will be covered in[10]. TEGÕ has been shown to be superior to detail later. Together these modifications alloweither activated clotting time (ACT) or conventional analysis of the functional importance of differenttests at diagnosing postoperative coagulopathies [11] components of the haemostatic system. This mayand can help predict post operative blood loss [12]. make specific diagnosis and targeting of therapy possible. Furthermore potential therapies can be tested on patient’s blood ex-vivo to predict theTEGÕ : Recent modifications clinical response before administration [13].Unmodified TEGÕ provides a non-specific assess-ment of global haemostasis; the effects of some Limitations of TEGÕabnormalities are obscured by other more dominantcomponents of the coagulation system (such as Haemostasis is associated with a wide rangethrombin). Recent modifications to TEGÕ allow of normal values due to extensive variability inmore precise identification of abnormalities and have components of the haemostatic system includingimproved its ease of use and reproducibility (see platelet count and function, GPIIb/IIIa receptorTable II). number and fibrinogen concentration. Ideally there- Modifications include using sample activators to fore, each patient should have baseline TEGÕspeed up result acquisition, and citrated samples to measurements before initiating a treatment orallow a longer delay before testing [13–15]. procedure so that there is an internal, individualizedAlternatively blood can be taken into heparinised reference for change. Difficulties with validation andtubes, again allowing a longer delay before testing standardization probably accounts for why TEGÕand also eliminating the effect of thrombin, allowing has not been universally accepted by haematologistsassessment of the contribution of platelets and fibrin [15]. To some extent these issues have been over-to the clot. The addition of a platelet glycoprotein come by the use of computer software to analyse theIIb/IIIa (GPIIb/IIIa) inhibitor in vitro inhibits plate- TEGÕ trace which allows for standardization oflet aggregation and allows the relative contribution of results. Further standardization has been achieved byfibrinogen to haemostasis to be assessed. The TEGÕ use of disposable cups and pins, individual tempera-trace produced in this context correlates with the ture control and use of activators such as kaolin toplasma fibrinogen concentration [16]. Other mod- standardize the initiation of the clotting process. Oneifications (including the use of specific platelet fundamental challenge relating to the potential clinical applicability of TEGÕ is whether it is only useful in the assessment of a change in clotting Table II. Modifications to standard TEGÕ . behaviour, or whether ‘‘snapshot’’ values will beReagent used Rationale for use useful.Citrate Enables prolonged storage of samples before analysis. Current clinical applicationsHeparin Inhibits thrombin allowing the contribution of fibrin One of the main roles of TEGÕ in clinical practice is and platelets to be assessed. in hepatobiliary surgery where it is used to monitorHeparinase Reverses the effect of heparin, haemostasis and guide therapy [17]. It has been e.g. in patients on shown to be more effective than conventional tests at cardiopulmonary bypass.Activators (e.g. Celite, Speed up result acquisition. assessing the risk of bleeding in this complex area Kaolin, Tissue Factor) [18, 19]. TEGÕ has been used in liver transplanta-Glycoprotein Inhibit platelet function allowing tion since 1980 where it has been shown to reduce IIb/IIIa inhibitors the contribution of fibrinogen transfusion requirements [16]. In obstetrics TEGÕ to be assessed. can be used to differentiate between the normalAntifibrinolytic drugs Reverse fibrinolysis. (e.g. Tranexamic acid) hypercoagulable state in pregnancy and the coagulo-Activator FTM (Reptilase Activates fibrin formation pathic hypercoagulable state associated with pre- and Factor XIIIa) without affecting platelets. eclampsia. TEGÕ has also been applied to obstetricArachidonic Acid Activates platelets via the patients to identify those at risk of potentially production of thromboxane dangerous bleeding from an epidural [20]. A2. This pathway is affected by aspirin. In cardiac surgery it is well established that CPBADP Activates platelets via P2Y1 (cardio-pulmonary bypass) disturbs the haemostatic and P2Y12 receptors. system in a number of ways including (i) haemodilu- Clopidogrel and other tion of procoagulants, fibrinogen and platelets [21], thienopyridines inhibit the (ii) a reduction in levels of coagulation factors, (iii) the P2Y12 ADP receptor. use and reversal of heparin, (iv) preoperative
  • 512 A. R. Hobson et al.administration of platelets [22], (v) altered termpera- to antiplatelet agents might allow additional antiplate-ture and (vi) surface interaction in the bypass circuit. let therapy to be administered with the aim ofIt has been demonstrated that routine use of TEGÕ reducing events in these patients [26].during cardiac surgery reduces transfusion require- Historical methods of measuring platelet activationments and, in addition, when transfusion was and function are time consuming and cannot berequired, the TEGÕ group were able to employ performed at the bedside. Conventional tests mea-more specific therapy by identifying the cause of the sure parameters such as platelet numbers andcoagulopathy [9]. TEGÕ can also be useful in the isolated platelet function outside the context of clotintraoperative period; for example, the use of hepar- formation. Optical aggregation is the gold standardinase in perioperative TEGÕ studies is able to method. However, it is performed only in specializedneutralize the effects of heparin administered during situations due to the cost and expertise required andCPB. Further, hypothermia used in CPB can affect hence is not suitable as a rapid point of care test [27].coagulation in ways not detected by standard coagu- Recently several assays have been developed whichlation tests. In contrast, temperature adapted TEGÕ show some potential as point of care tests of thecan detect abnormalities in the hypothermic patient effects of antiplatelet medication. These includeenabling effective treatment of coagulopathy [23]. the PFA-100 (Dade Behring, Deerfield, Illinois, As well as its use in the management of haemo- USA), the Accumetrics VerifyNow systemstasis TEGÕ has more recently been investigated as a (Accumetrics, San Diego, California, USA),marker of risk for thrombotic events. In a study of Plateletworks (Helena Laboratories, Allen Park,240 non-cardiac post-operative patients there was a Michigan, USA) and the Cone and Plate(let)significantly higher incidence of thrombotic events, analyser (DiaMed, Canton, Ohio, USA) as well asincluding myocardial infarction, in those with max- the modified TEGÕ platelet mapping system.imum amplitude (MA) of 468 mm on TEGÕ [24]. The PFA-100 is a whole blood assay that measuresGurbel et al. have also shown that increased MA on the time for occlusion of an aperture in a membraneTEGÕ (both pre- and post-clopidogrel loading at the under high stress shear conditions, mimicking thetime of procedure) provides a predictive tool for forces in a stenotic artery. A cartridge containing aischaemic events following PCI. On combining two membrane coated with collagen and epinephrine hasmeasures from a standard TEGÕ trace, MA and a been used to study the effects of aspirin. There isshort R time (see Figure 2) they demonstrated an some evidence of a higher incidence of clinical eventsodds ratio for ischaemic events in the 6 months in patients found not to respond to aspirin by PFA-following PCI of 38 [25]. 100 [28]. However, the PFA-100 is not a clear indicator of the effects of clopidogrel [29]. In addition the result depends on von Willebrandt’sAssessment of the effects of factor, which is itself increased by PCI [30]. It mayantiplatelet therapy therefore not be able to differentiate betweenAs our understanding of the pathophysiology of increased platelet reactivity due to PCI and avascular events (for example in acute coronary reduced response to aspirin.syndromes (ACS) and stent thrombosis) has evolved The Accumetrics VerifyNow system is a rapid,the integral role of the platelet is increasingly automated whole blood assay that measures aggluti-recognized. Plaque rupture, platelet activation and nation of fibrinogen-coated beads in response toaggregation and thrombus formation occur as a specific agonists for aspirin, the P2Y12 receptorresult of complex interactions between platelets, (for thienopyridines) and Glycoprotein IIb/IIIa inhi-vascular endothelium, inflammatory cells and circu- bitors. In the setting of PCI aspirin and clopidogrellating proteins. These processes can result in vascular resistance as measured by Accumetrics hasocclusion, ischaemia and infarction. Similarly, coro- been correlated with an increased incidence of peri-nary vessel trauma and inflammation induced during procedural myocardial infarction [31, 32]. However,the process of stent implantation, as well as the the utility of the aspirin and clopidogrel assays ispoorly understood subsequent role of stent endothe- limited in some emergency patients as their use is notlialisation combine to make some patients suscep- recommended within 2 weeks of abciximab therapy.tible to stent thrombosis. The plateletworks system uses collection tubes with A rapid and reliable method of assessing the EDTA as baseline and collagen and ADP agonists,contribution of platelets to clotting would be of which are then examined in a standard cell counter.considerable clinical value. Such a test would enable This system is not yet well studied but there is somethe optimization of antiplatelet therapy on an individ- evidence for its use in detecting responses toual patient basis. Conventional treatment with aspirin thienopyridines and glycoprotein IIb/IIIa inhibitors.and clopidogrel involves administration of standard The pros, cons and evidence base for these tests aredoses to all patients, despite the well established summarized in Table III.evidence that responses, in terms of platelet function, In standard TEGÕ the maximum amplitude (MA)are heterogeneous. Identification of patients resistant is largely dependent on thrombin. Thrombin is a
  • Table III. A comparison of currently utilised point of care ‘‘platelet function’’ assays. Ability to Ability to monitor Correlation Correlation Ability to monitor GPIIb/IIIa with clinical with opticalTest Pros Cons monitor aspirin clopidogrel antagonist events aggregationPFA-100 Ease of use. Whole blood assay, Depends on Von Willebrand Yes No Yes No No high shear stress. factor (which is elevated by PCI).Accumetrics Ease of use, automated, rapid, Uncertain sensitivity, specificity. Yes Yes Yes Yes Yes whole blood assay.Plateletworks Whole blood assay. Ease of use. Difficulties with aspirin and No Yes Yes No Yes clopidogrel assays in emergency patients.Modified TEGÕ Widespread utility. Requires cell counter. Little evidence Yes Yes Yes Yes Yesplatelet mapping kit for use. Some sample preparation. Thrombelastography 513
  • 514 A. R. Hobson et al.powerful platelet activator and overwhelms the effect antiplatelet agents, (ii) facilitate tailoring these agentsof other less potent platelet activators such as to an individual and (iii) optimize withdrawal ofArachidonic Acid (AA) and adenosine diphosphate antiplatelet therapy for surgical purposes [36]. As(ADP). In the presence of thrombin it is possible to platelet activation can persist for many months after adetect some effect from potent antiplatelet agents cardiovascular event [39, 40], TEGÕ assessment ofsuch as Glycoprotein IIb/IIIa inhibitors [33], but the this activation could tailor future management witheffect of other antiplatelet agents remains obscured regard to the timescale of treatment with antiplatelet[34]. However, by taking blood into a tube that agents. Of course, antiplatelet therapy does increasecontains heparin, thrombin is inhibited. The sub- the risk of bleeding; these risks and the requirementsequent addition of Activator FTM generates a fibrin for platelet transfusion could be reduced by ex-vivonetwork in which platelets can interact independent monitoring of platelet function [41].of thrombin. Without alternative sources of plateletactivation there is minimal platelet activation and Aspirin and clopidogrel resistance – potential targetstherefore minimal response on the TEGÕ curve (low for diagnosis and treatment in clinical practiceMA). However, other platelet activators (AA orADP) can be added and (in the absence of inhibition Aspirin causes platelet inhibition by irreversibleof their specific pathways of action (e.g. with aspirin acetylation of cyclooxygenase-1 preventing conver-or clopidogrel respectively)) this increases the MA. sion of AA to prostaglandin –H and subsequentMaximal platelet activation generates a curve similar formation of the potent vasoconstrictor and plateletto unmodified TEGÕ in the presence of thrombin. activator thromboxane A2. It is well established thatThe effect of antiplatelet medication can therefore be long-term use of aspirin in patients with vascularestablished by comparing the unmodified TEGÕ disease decreases morbidity and mortality fromcurve (representing maximal platelet activation) and cardiovascular events by 25% and it is a cornerstonethe modified TEGÕ curve with either AA or ADP of secondary prevention treatment in the setting ofstimulation. coronary artery disease [42]. The role of aspirin in Aspirin achieves platelet inhibition by permanent primary prevention is still the subject of debate,inactivation of cyclooxygenase I, an enzyme in although most trials support its use in high-riskplatelet AA metabolism. The percent inhibition due patients [43]; the potential benefit must, however, beto aspirin can therefore be calculated by comparing balanced with risk of bleeding.the unmodified curve in the presence of thrombin The anti-thrombotic effect of aspirin is saturable at(maximal platelet activation), the heparinised sample doses in the range of 75–100 mg in normal adultswith Act F alone (no platelet activation) and the [44]. Aspirin resistance is a genuine entity althoughmodified TEGÕ curve with AA stimulation (residual difficult to define precisely and is reported in up toplatelet activation due to AA in the presence of 20% of patients with stable coronary artery diseaseaspirin). [45–47]. Recent studies using methods which The effect of Clopidogrel, a direct ADP inhibitor specifically analyse platelet aggregation to AAand the GPIIb/IIIa antagonist, abciximab, on plate- (including modified TEGÕ ) suggest that the truelets can be assessed in a similar fashion, utilizing incidence may be much lower [48, 49]; these studiesADP-induced platelet aggregation. These modifica- have also highlighted the importance of compliance.tions are summarized in Table II. This system is Patients shown to be resistant to aspirin have highermarketed by Haemoscope as the ‘‘Platelet Mapping rates of cardiovascular events [49]. Platelets fromKit’’. Experiments by our group have established the aspirin-resistant patients also appear to be moreutility of modified TEGÕ in detecting time depen- sensitive to the actions of ADP so that the addition ofdent effects of antiplatelet therapy in healthy volun- alternative antiplatelet therapies that inhibit ADP-teers [35]. With these modifications TEGÕ correlates induced platelet aggregation to these patients isclosely with optical aggregation in the assessment of therapeutically useful [50]. It is possible thatthe effects of antiplatelet agents [36]. In the context increased sensitivity to ADP and other plateletof PCI Mobley et al. found a good correlation activators explains why assays that are not entirelybetween the two techniques when used to detect the specific to AA induced activation give highereffects of clopidogrel [37]. A close correlation estimates on the incidence of aspirin resistance.between modified TEGÕ and optical aggregation Clopidogrel is a thienopyridine derivative that bothhas also been found when used in the detection of selectively inhibits ADP-induced platelet aggregationaspirin resistance [38]. and inhibits the conformational change of platelet GPIIb/IIIa so that fibrinogen can no longer bind to this receptor; Clopidogrel has no direct effects on theEffects of antiplatelet agents on platelet metabolism of AA. The CAPRIE trial suggested thatfunction – in clinical practice clopidogrel was marginally more effective thanAn easy, functional test of the effects of antiplatelet aspirin in prevention of vascular events in a high-therapy on clotting would (i) identify resistance to risk population [51]. Data from CURE suggest that
  • Thrombelastography 515Figure 3. Angiogram (AP projection) of a left coronary artery showing proximal left anterior descending artery (LAD) stent after insertionon the left and following proximal stent thrombosis and LAD occlusion on the right.the addition of clopidogrel to aspirin in patients with stents (DES). Key to this strategy has been the use ofACS conveys prognostic benefit by reducing further clopidogrel and aspirin to reduce the rate of stentcardiovascular events [52]. Recently CHARISMA thrombosis [58]. However there are importanthas suggested a benefit with the addition of ongoing concerns over stent thrombosis, whichclopidogrel to aspirin in all patients with symptom- continues to occur in 1–2% of cases in clinicalatic atherosclerosis although there was a suggestion practice and may be associated with mortality rates ofof harm in those with asymptomatic disease or up to 45% [59] (Figure 3). Specifically, there havemultiple cardiovascular risk factors alone [53]. also been reports of late thrombosis occurring afterThere is, however, considerable inter-individual DES implantation particularly on reduction orvariability in platelet inhibition in response to cessation of antiplatelet therapy [60]. Importantly,clopidogrel [54]. Patients with a raised body mass altered responses to aspirin and clopidogrel have alsoindex (BMI) and those with type two diabetes been shown to convey an increased risk of stentmellitus have an increased sensitivity in platelet thrombosis [61]. Such patients may require largeradhesion and aggregation to ADP [55]. Increased doses of aspirin and clopidogrel or alternative orthromboxane production, increased GPIIb/IIIa additional antiplatelet therapy to provide adequatereceptor expression, greater thrombin generation therapeutic protection. However, clinical practice isand an attenuated response to the inhibitory effect currently limited by the lack of a rapid, easilyof aspirin on platelets have also been reported [56]. accessible point of care test to assess such issues.Mobley et al. have demonstrated (using optical The discrepancy between the estimated rates ofaggregation, Ichor plateletworks assay and TEGÕ ) aspirin and clopidogrel resistance using tests thatthat 30% of patients undergoing coronary angio- specifically assess isolated platelet function andgraphy were resistant to clopidogrel [37]. preliminary investigations using modified TEGÕClopidogrel resistance (using ADP-induced optical may suggest some advantage of assessing ex vivoplatelet aggregation) has been shown to be associated clotting as a complete entity [38].with increased risk of recurrent thrombotic events in Whilst it is still unclear to what extent variation inpatients with acute myocardial infarction [57]. platelet function tests performed in isolation corre-Recently Gurbel et al. have shown in patients post late with genuine effects on clotting tendency thePCI that the degree of ADP induced platelet current strategy of universally applied loading andaggregation (by light transmittance aggregometry) maintenance doses of antiplatelet agents for allwas significantly more pronounced in those with patients with CAD, including those undergoingsubsequent ischaemic events [25]. PCI, is likely to be flawed. Some patients have a PCI is now the commonest method of coronary weak response and lack therapeutic protection,revascularisation in the UK. The initial relatively whereas others have an excessive response and arecommon limitation of restenosis and the subsequent more susceptible to bleeding [62]. It remains to beneed for repeat revascularisation in patients treated established if identifying patients who appear to lackwith bare metal stents has been dramatically reduced therapeutic protection and modifying their subse-as a result of widespread deployment of drug eluting quent treatment would improve outcome.
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